Despite progress in lymphoid malignancies, most are still incurable and lead to the death of the patient. The University of Iowa/Mayo Clinic Lymphoma SPORE (UI/MC SPORE) is a highly successful translational research program that takes advantage of the combined strengths of the translational lymphoma programs of the Holden Comprehensive Cancer Center at the University of Iowa and the Mayo Clinic Comprehensive Cancer Center - two NCI-designated comprehensive cancer centers. During the prior funding period, the UI/MC has been highly productive. Scientific accomplishments include translational studies exploring the potential of a novel therapeutic agent, immunostimulatory CpG ODN, as a potential treatment for B cell malignancies, development of novel approaches to imaging that could impact on our understanding of lymphoma biology, and investigation into biomarkers that could have a significant impact on management of lymphoma. Five early phase therapeutic clinical trials have been opened as part of the UI/MC SPORE, including four studies that have accrued subjects at both Iowa and Mayo. Since initiation of the UI/MC SPORE in 2002, 96 subjects have been enrolled on therapeutic trials and 17 on novel imaging trials. DNA and extensive clinical data have been collected on 1331 subjects at Iowa and Mayo as part of the UI/MC Lymphoma SPORE Molecular Epidemiologic Resource which will be increasingly valuable as a tool for identifying genetic factors that contribute to lymphomagenesis and response to therapy. This renewal application is designed to accelerate the progress of the UI/MC SPORE and consists of four research projects, four core resources, and the Career Development and Developmental Research Programs. Specific projects are as follows: 1) A novel approach to the immunotherapy of B cell malignancies 2) Signal transduction inhibitor therapy for lymphoma 3) Biology and Epidemiology of APRIL and BLyS in B-cell NHL 4) Regulatory T-cells in the tumor microenvironment of B-cell non-Hodgkin lymphoma Core resources include Administration, Biostatistics and Bioinformatics, Biospecimens, and Clinical Research that supports both clinical trials and the Molecular Epidemiology Resource of the UI/MC SPORE. All units within the UI/MC SPORE work to draw on the resources of both institutions to expedite the translation of discoveries into new and better approaches to the prevention and treatment of lymphoma.